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    Polymeric carriers linked to nucleotide analogues via a phosphoramide bond
    1.
    发明授权
    Polymeric carriers linked to nucleotide analogues via a phosphoramide bond 失效
    通过磷酰胺键与核苷酸类似物连接的聚合载体

    公开(公告)号：US5981507A

    公开(公告)日：1999-11-09

    申请号：US766597

    申请日：1996-12-12

    申请人： Lee Josephson ,  Ernest V. Groman ,  Yong-Qian Wu

    发明人： Lee Josephson ,  Ernest V. Groman ,  Yong-Qian Wu

    IPC分类号： A61K47/48 ,  A01N43/04

    CPC分类号： A61K47/48038 ,  A61K47/4823 ,  A61K47/48315

    摘要： Novel compositions of nucleotide analog prodrugs for the treatment of viral infections and cancer are herein disclosed. The prodrugs have a biocompatible polymeric carrier conjugated to the nucleotide analog via an amino-phosphate linkage. The amino group is provided by the carrier, which either inherently possesses a primary amine, or is modified with reactive groups that incorporate the primary amine onto the carrier. The carrier can be a polyamino acid, a polyvinylic polymer, a polysaccharide or combinations thereof, such as polylysine, HPMA, dextran, hydroxyethyl starch, or polyethylene glycol; the nucleotide analog can be ribavirin araA, AZT, acyclovir, 5-FUDR, araC or ddI. Methods of treating a viral infection of cancer using these prodrugs are also disclosed. The prodrugs endow the nucleotide analogs with substantially enhanced therapeutic efficacy and reduces toxicity in comparison to the nucleotide analog alone.

    摘要翻译： 本文公开了用于治疗病毒感染和癌症的核苷酸类似物前药的新型组合物。 前药具有通过氨基 - 磷酸键连接至核苷酸类似物的生物相容性聚合物载体。 氨基由载体提供，其本身具有伯胺，或者由将伯胺掺入到载体上的反应性基团进行改性。 载体可以是聚氨基酸，聚乙烯基聚合物，多糖或其组合，例如聚赖氨酸，HPMA，葡聚糖，羟乙基淀粉或聚乙二醇; 核苷酸类似物可以是利巴韦林araA，AZT，阿昔洛韦，5-FUDR，araC或ddI。 还公开了使用这些前药治疗癌症病毒感染的方法。 与单独的核苷酸类似物相比，前药使核苷酸类似物具有显着增强的治疗功效并降低毒性。

    Hydrated biodegradable superparamagnetic metal oxides
    2.
    发明授权
    Hydrated biodegradable superparamagnetic metal oxides 失效
    水合生物降解超顺磁金属氧化物

    公开(公告)号：US5219554A

    公开(公告)日：1993-06-15

    申请号：US863360

    申请日：1992-03-31

    申请人： Ernest V. Groman ,  Lee Josephson ,  Jerome M. Lewis

    发明人： Ernest V. Groman ,  Lee Josephson ,  Jerome M. Lewis

    IPC分类号： A61K49/18 ,  C08G18/18 ,  C08G18/20 ,  C08G18/24 ,  C08G18/26 ,  C08J9/14 ,  G01R33/28

    CPC分类号： G01R33/5601 ,  A61K49/18 ,  A61K49/1836 ,  A61K49/1863 ,  B82Y5/00 ,  C08G18/1808 ,  C08G18/1816 ,  C08G18/1825 ,  C08G18/2036 ,  C08G18/246 ,  C08G18/26 ,  C08J9/144 ,  C08G2101/00 ,  C08J2375/04 ,  Y10T436/24

    摘要： This invention relates to materials exhibiting certain magnetic and biological properties which make them uniquely suitable for use as magnetic resonance imaging (MRI) agents to enhance MR images of animal organs and tissues. More particularly, the invention relates to the in vivo use of biologically degradable and metabolizable superparamagnetic metal oxides as MR contrast agents. Depending on their preparation, these metal oxides are in the form of superparamagnetic particle dispersoids or superparamagnetic fluids where the suspending medium is a physiologically-acceptable carrier, and may be uncoated or surrounded by a polymeric coating to which biological molecules can be attached. These materials are administered to animals, including humans, by a variety of routes and the metal oxides therein collect in specific target organs to be imaged; in the case of coated particles, the biological molecules can be chosen to target specific organs or tissues. The biodistribution of the metal oxides in target organs or tissues results in a more detailed image of such organs or tissues because the metal oxides, due to their superparamagnetic properties, exert profound effects on the hydrogen nuclei responsible for the MR image. In addition, the dispersoids and fluids are quite stable and, in the case of the fluids, can even be subjected to autoclaving without impairing their utility. Furthermore, the materials are biodegradable and, in the case of iron oxide compounds, can eventually be incorporated into the subject's hemoglobin, making them useful in treating anemia. Thus, the materials are well-suited for in vivo use.

    摘要翻译： 本发明涉及具有某些磁性和生物学特性的材料，使得它们独特地适用于磁共振成像（MRI）试剂以增强动物器官和组织的MR图像。 更具体地，本发明涉及生物可降解和代谢的超顺磁性金属氧化物作为MR造影剂的体内应用。 取决于它们的制备，这些金属氧化物是超顺磁性颗粒分散体或超顺磁性流体的形式，其中悬浮介质是生理上可接受的载体，并且可以是未涂覆的或被可附着生物分子的聚合物涂层包围。 这些材料通过各种途径施用于包括人在内的动物，并且其中的金属氧化物收集在要成像的特定靶器官中; 在涂覆颗粒的情况下，可以选择生物分子来靶向特定的器官或组织。 金属氧化物在靶器官或组织中的生物分布导致这种器官或组织的更详细的图像，因为金属氧化物由于其超顺磁性质对负责MR图像的氢原子发挥深远的作用。 此外，分散体和流体是相当稳定的，并且在流体的情况下，甚至可以进行高压灭菌而不损害它们的效用。 此外，材料是可生物降解的，并且在氧化铁化合物的情况下，最终可以并入受试者的血红蛋白中，使其可用于治疗贫血。 因此，这些材料非常适合于体内使用。

    Vascular magnetic resonance imaging agent comprising nanoparticles
    4.
    发明授权
    Vascular magnetic resonance imaging agent comprising nanoparticles 失效
    包含纳米颗粒的血管磁共振成像剂

    公开(公告)号：US5314679A

    公开(公告)日：1994-05-24

    申请号：US995111

    申请日：1992-12-22

    申请人： Jerome M. Lewis ,  Edward T. Menz ,  Francis E. Kenny ,  Ernest V. Groman ,  Lee Josephson

    发明人： Jerome M. Lewis ,  Edward T. Menz ,  Francis E. Kenny ,  Ernest V. Groman ,  Lee Josephson

    IPC分类号： A61K49/18 ,  C08G18/18 ,  C08G18/20 ,  C08G18/24 ,  C08G18/26 ,  C08J9/14 ,  G01R33/28 ,  A61B5/055 ,  A61K31/715 ,  A61K33/26 ,  A61K37/14

    CPC分类号： G01R33/5601 ,  A61K49/18 ,  A61K49/1863 ,  B82Y5/00 ,  C08G18/1808 ,  C08G18/1816 ,  C08G18/1825 ,  C08G18/2036 ,  C08G18/246 ,  C08G18/26 ,  C08J9/144 ,  C08G2101/00 ,  C08J2375/04 ,  Y10S436/806 ,  Y10T436/24

    摘要： The preparation and isolation of biodegradable superparamagnetic MR imaging contrast agents for the vascular compartment is described. These aggregates are comprised of individual biodegradable superparamagnetic metal oxide crystals which aggregates have an overall mean diameter less than about 4000 angstroms. The preferred vascular imaging contrast agent is comprised of aggregates of iron oxide crystals having an overall mean diameter less than about 500 angstroms. These contrast agents may be associated with a macromolecular species, which assist, among other things, in the preparation of these extremely small materials, and may be dispersed or dissolved in a physiologically acceptable medium. Preferred media also stabilize the materials against further aggregation even under harsh sterilization conditions. The autoclaved biodegradable superparamagnetic iron oxides of the invention are ideally suited for a pharmaceutical preparation and enjoy several advantages over prior intravascular imaging contrast media including low osmolality, low effective dose requirements, high relaxivities, long blood lifetimes, rapid biodegradability, and versatility with respect to a wide range of applicable MR data acquisition parameters.

    摘要翻译： 描述了用于血管隔室的可生物降解的超顺磁性MR成像造影剂的制备和分离。 这些聚集体由单个可生物降解的超顺磁金属氧化物晶体组成，其聚集体具有小于约4000埃的总平均直径。 优选的血管成像造影剂由总平均直径小于约500埃的氧化铁晶体的聚集体组成。 这些造影剂可以与大分子物质相关联，其特别有助于制备这些极小物质，并且可以分散或溶解在生理上可接受的介质中。 优选的介质甚至在恶劣的灭菌条件下也稳定材料以防止进一步聚集。 本发明的高压消毒的可生物降解的超顺磁铁氧化物理想地适用于药物制剂，并且比先前的血管内成像造影剂具有若干优点，包括低渗透压浓度，低有效剂量要求，高松弛度，长血液寿命，快速生物降解性和相对于 广泛的适用MR数据采集参数。

    Solvent mediated relaxation assay system
    5.
    发明授权
    Solvent mediated relaxation assay system 失效
    溶剂介导的松弛测定系统

    公开(公告)号：US5254460A

    公开(公告)日：1993-10-19

    申请号：US695378

    申请日：1991-05-03

    申请人： Lee Josephson ,  Edward T. Menz ,  Ernest V. Groman

    发明人： Lee Josephson ,  Edward T. Menz ,  Ernest V. Groman

    IPC分类号： G01N33/543 ,  G01N33/66 ,  G01N33/53

    CPC分类号： G01N33/54333 ,  G01N33/54373 ,  G01N2333/42 ,  G01N2333/765 ,  G01N2400/22 ,  G01N33/66 ,  Y10S436/806 ,  Y10T436/24

    摘要： A new ligand binding assay is based upon measurements of relaxation rates of the solvent, which are obtained with a magnetic resonance (MR) spectrometer. It is termed a solvent mediated relaxation assay system (SMRAS). SMRAS is based on the observation that the enhancement of proton relaxation rates produced by a magnetic material can be modulated by the binding of various analytes to a magnetic material. Hence the relaxation rate of the solvent can be interpreted to give information on the concentration of an analyte.

    摘要翻译： 新的配体结合测定法是基于用磁共振（MR）光谱仪获得的溶剂的松弛速率的测量。 称为溶剂介导的松弛测定系统（SMRAS）。 SMRAS基于这样的观察，可以通过将各种分析物与磁性材料的结合来调节由磁性材料产生的质子弛豫速率的增强。 因此，可以解释溶剂的松弛速率以提供关于分析物浓度的信息。

    Hepatocyte specific composition and their use as diagnostic imaging agents
    7.
    发明授权
    Hepatocyte specific composition and their use as diagnostic imaging agents 失效
    异丝氨蛋白受体特异性组合物及其作为MRI造影剂的用途

    公开(公告)号：US5352432A

    公开(公告)日：1994-10-04

    申请号：US917567

    申请日：1992-07-20

    申请人： Edward T. Menz ,  Jeffrey M. Rothenberg ,  Ernest V. Groman ,  Lee Josephson

    发明人： Edward T. Menz ,  Jeffrey M. Rothenberg ,  Ernest V. Groman ,  Lee Josephson

    IPC分类号： A61K49/18 ,  C08G18/18 ,  C08G18/20 ,  C08G18/24 ,  C08G18/26 ,  C08J9/14 ,  G01R33/28 ,  A61B5/055 ,  A61K31/715 ,  A61K33/26

    CPC分类号： A61K49/18 ,  A61K49/1806 ,  A61K49/1863 ,  A61K49/1866 ,  A61K49/1869 ,  B82Y5/00 ,  C08G18/1808 ,  C08G18/1816 ,  C08G18/1825 ,  C08G18/2036 ,  C08G18/246 ,  C08G18/26 ,  C08J9/144 ,  G01R33/5601 ,  C08G2101/00 ,  C08J2375/04 ,  Y10S436/806 ,  Y10T436/24

    摘要： A new class of magnetic resonance (MR) contrast agents are described whose in vivo biodistribution is based upon the ability of certain cells to recognize and internalize macromolecules, including the MR contrast agents of the present invention, via a process which substantially involves receptor mediated endocytosis. The RME-type MR contrast agents described herein comprised of biodegradable superparamagnetic metal oxides associated with a variety macromolecular species, including but not limited to, serum proteins, hormones, asialoglycoproteins, galactose-terminal species, polysaccharides, arabinogalactan, or conjugates these molecules with other polymeric substances such as a poly(organosilane) and dextran. One of the advantages or these MR contrast agents is that they may be selectively directed to those cells which bear receptors for a particular macromolecule or ligand and are capable of undergoing receptor mediated endocytosis. An MR contrast agent prepared from biodegradable superparamagnetic iron oxide and asialofetuin, or more preferably arabinogalactan, for example, is selectively localized in the hepatocytes the liver with no significant accumulation in the spleen. An MR experiment which can be carried out shortly after administration to the subject of the contrast agents of the invention can thus provide a method for obtaining an enhanced MR image, as well as valuable information regarding the functional or metabolic state of the organ or tissue under examination. Preparative methods, biodistribution data, and time function MR images are further provided.

    摘要翻译： 描述了一类新的磁共振（MR）造影剂，其体内生物分布基于某些细胞通过基本上涉及受体介导的内吞作用的方法识别和内化大分子（包括本发明的MR造影剂）的能力， 。 本文描述的RME型MR造影剂包括与多种大分子物质相关的可生物降解的超顺磁性金属氧化物，包括但不限于血清蛋白，激素，脱唾液酸糖蛋白，半乳糖末端物质，多糖，阿拉伯半乳聚糖，或将这些分子与其他 聚合物质如聚（有机硅烷）和葡聚糖。 这些MR造影剂的一个优点是它们可以选择性地定向到承载特定大分子或配体的受体的细胞，并且能够进行受体介导的内吞作用。 例如，由可生物降解的超顺磁性氧化铁和脱唾液酸铁蛋白制备的MR造影剂，或更优选阿拉伯半乳聚糖，选择性地定位在肝脏的肝细胞中，在脾脏中没有显着的积累。 因此，可以在给予本发明的造影剂的受试者后不久进行的MR实验可以提供获得增强的MR图像的方法，以及关于器官或组织的功能或代谢状态的有价值的信息 检查。 还提供了制备方法，生物分布数据和时间函数MR图像。

    Filter sterilization for production of colloidal, superparamagnetic MR contrast agents
    9.
    发明授权
    Filter sterilization for production of colloidal, superparamagnetic MR contrast agents 失效
    过滤灭菌用于生产胶体超顺磁性MR造影剂

    公开(公告)号：US5160726A

    公开(公告)日：1992-11-03

    申请号：US650957

    申请日：1991-02-05

    申请人： Lee Josephson ,  Ernest V. Groman ,  Stephen Palmacci

    发明人： Lee Josephson ,  Ernest V. Groman ,  Stephen Palmacci

    IPC分类号： A61K49/18 ,  A61L2/00 ,  A61L2/025

    CPC分类号： A61K49/1863 ,  A61K49/1809 ,  A61L2/0017 ,  A61L2/025 ,  Y10S436/806 ,  Y10S514/836 ,  Y10T436/24

    摘要： An improvement is provided to a method for obtaining an in vivo MR image of an organ or tissue of an animal or human subject, of the type including administering to the subject as a contrast agent to enhance such MR image an effective amount of a colloid including superparamagnetic metal oxide particles dispersed in a physiologically acceptable carrier. In accordance with the improvement, the method includes preparing the colloid in a manner that provides a reduction in toxicity in comparison with that associated with administration of the colloid after terminal sterilization. The improvement may include sterilizing the colloid by filtration. In an additional embodiment, the colloid may be sterilized by filtration and preserved by lyophilization. The colloid may be lyophilized in the presence of a compatible excipient. The excipient utilized may include a dextran or a citrate anion. Other embodiments include related compositions and methods.

    摘要翻译： 提供了一种用于获得动物或人类受试者的器官或组织的体内MR图像的方法的改进，包括以对象作为造影剂施用以增强这种MR图像有效量的胶体，包括 分散在生理上可接受的载体中的超顺磁金属氧化物颗粒。 根据改进，该方法包括以与末端灭菌后的胶体的施用相关的方式，提供毒性降低的方式制备胶体。 改进可包括通过过滤对胶体进行消毒。 在另外的实施方案中，胶体可以通过过滤灭菌并通过冻干保存。 胶体可以在相容的赋形剂存在下冻干。 所用的赋形剂可以包括葡聚糖或柠檬酸盐阴离子。 其他实施方案包括相关的组合物和方法。